Summary for the Nobel Prize in Medicine, 1999
A large number of proteins carrying out essential functions are constantly
being made within our cells. These proteins have to be transported either
out of the cell, or to the different compartments - the organelles - within
the cell. How are newly made proteins transported across the membrane
surrounding the organelles, and how are they directed to their correct
location?
These questions have been answered through the work of this year's Nobel
Laureate in Physiology or Medicine, Dr Gunter Blobel, a cell and molecular
biologist at the Rockefeller University in New York. Already at the
beginning of the 1970s he discovered that newly synthesized proteins have
an intrinsic signal that is essential for governing them to and across the
membrane of the endoplasmic reticulum, one of the cell's organelles. During
the next twenty years Blobel characterized in detail the molecular
mechanisms underlying these processes. He also showed that similar "address
tags", or "zip codes", direct proteins to other intracellular organelles.
The principles discovered and described by Gunter Blobel turned out to be
universal, operating similarly in yeast, plant, and animal cells. A number
of human hereditary diseases are caused by errors in these signals and
transport mechanisms. Blobel's research has also contributed to the
development of a more effective use of cells as "protein factories" for the
production of important drugs.
Several important functions
An adult human being is made up of approximately 100,000 billion cells. A
cell contains many different compartments, organelles, each surrounded by a
membrane. The organelles are specialized to carry out different tasks. The
cell nucleus, for instance, contains the genetic material (DNA) and thus
governs all functions of the cell. The mitochondria are the "power plants"
producing energy needed by the cell, and the endoplasmic reticulum is,
together with the ribosomes, responsible for synthesizing proteins.
Every cell contains approximately one billion protein molecules. The
different proteins have a large number of important functions. Some
constitute the building blocks for constructing the cell while others
function as enzymes catalyzing thousands of specific chemical reactions.
The proteins within a cell are constantly degraded and resynthesized. The
number of amino acids - the building blocks making up all proteins - may in
a single protein range from about 50 to several thousands, forming long,
folded chains.
How do proteins cross the barriers?
Thus, it was for a long time a puzzle how large proteins could traverse the
tightly sealed, lipid-containing, membranes surrounding the organelles.
Some decades ago, it was also unknown how newly made proteins were directed
to their correct locations in the cell.
G̹nter Blobel was going to solve both of these puzzles. At the end of the
1960s he joined the famous cell biology laboratory of George Palade at the
Rockefeller Institute in New York. Here, during two decades, scientists had
studied the structure of the cell and the principles for the transport of
newly synthesized proteins out of the cell. This work earned George Palade
the Nobel Prize in Physiology or Medicine in 1974 (which he shared with the
Belgian scientists Albert Claude and Christian de Duve).
"The signal hypothesis"
Gunter Blobel's research was built on the traditions of Paladeå«s
laboratory. In particular, Blobel studied how a newly made protein,
destined to become transported out of the cell, is targeted to a
specialized intracellular membrane system, the endoplasmic reticulum. In
1971 he formulated a first version of the "signal hypothesis". He
postulated that proteins secreted out of the cell contain an intrinsic
signal thatgoverns them to and across membranes.
Based on elegant biochemical experiments, Blobel described in 1975 the
various steps in these processes. The signal consists of a peptide, i.e. a
sequence of amino acids in a particular order that form an integral part of
the protein. He also suggested that the protein traverses the membrane of
the endoplasmic reticulum through a channel (Fig. 1). During the next
twenty years, Blobel and coworkers step by step characterized the molecular
details of these processes. Eventually it was shown that the signal
hypothesis was both correct and universal, since the processes operate in
the same way in yeast, plant, and animal cells.
"Address tags" for organelle localization
In collaboration with other research groups, Gunter Blobel was soon able to
show that similar intrinsic signals target the transport of proteins also
to other intracellular organelles. On the basis of his results, Gunter
Blobel formulated in 1980 general principles for the sorting and targeting
of proteins to particular cell compartments. Each protein carries in its
structure the information needed to specify its proper location in the
cell. Specific amino acid sequences (topogenic signals) determine whether a
protein will pass through a membrane into a particular organelle, become
integrated into the membrane, or be exported out of the cell.
A range of signals that govern proteins to the different parts of the cell
have now been identified, showing that the principles formulated by Blobel
are correct. These signals can be compared to address tags or zip codes
which ensure that a traveler's luggage arrives at the correct destination,
or a letter reaches its correct addressee. These signal sequences are in
fact a chain of different amino acids present either as a short "tail" at
one end of the protein, or sometimes located within the protein.
Significance of Blobel's discovery
Gunter Blobel's discovery has had an immense impact on modern cell
biological research. When a cell divides, large amounts of proteins are
being made and new organelles are formed. If the cell is to function
correctly, the proteins have to be targeted to their proper locations.
Blobelå«s research has substantially increased our understanding of the
molecular mechanisms governing these processes. Furthermore, knowledge
about the topogenic signals has increased our understanding of many
medically important mechanisms. For example, our immune system uses
topogenic signals, e.g. in the production of antibodies.
Blobel's research has helped explain the molecular mechanisms behind
several genetic diseases. If a sorting signal in a protein is changed, the
protein could end up in a wrong location in the cell. One example is the
hereditary disease primary hyperoxaluria, which causes kidney stones
already at an early age. In some forms of familial hypercholesterolemia, a
very high level of cholesterol in the blood is due to deficient transport
signals. Other hereditary diseases, e.g. cystic fibrosis, are caused by the
fact that proteins do not reach their proper destination.
Future applications
In the near future the entire human genome will be mapped. As a result one
can also deduce the structure and topogenic signals of the proteins. This
knowledge will increase our understanding of processes leading to disease
and can be used to develop new therapeutic strategies. Already today drugs
are produced in the form of proteins, e.g. insulin, growth hormone,
erythropoetin and interferon. Usually bacteria are used for the production
of the drug, but in order to be functional certain human proteins need to
be synthesized in more complex cells, such as yeast cells. With the help of
gene technology the genes of the desired proteins are provided with
sequences coding for transport signals. The cells with the modified genes
can then be
efficiently used as protein factories.
Increased knowledge about the process by which proteins are being directed
to different parts of the cell also makes it possible to construct new
drugs that are targeted to a particular organelle to correct a specific
defect. The ability to reprogram cells in a specific way will also be
important for future cell and gene therapy.
Art
http://geology.swau.edu